1. Field of the Invention
The invention generally relates to the titration of multi-modality therapy regimens. In particular, the invention provides methods of titrating and evaluating multi-modalitiy therapy regimens using an evolutionary operation (EVOP) approach.
2. Background of the Invention
The use of multiple medications and/or treatment modalities in the treatment of individual patients is an increasingly commonplace occurrence. The elderly population, who consume the most drugs and in whom relative drug consumption continues to increase, is rapidly growing in the United States and other developed nations. The pace of new drug development, from drug discovery to drug production, has accelerated greatly, and single diseases are now treated with multiple drugs targeting different biochemical pathways or different aspects in the pathophysiology of a disease. This increase in drug consumption brings with it a dramatic increase in the potential for drug interactions and adverse drug reactions. New approaches to treatment and prescribing are needed to address these increasingly complicated dosing regimens.
Dose titration with single compounds is a relatively straightforward process employed by physicians to identify appropriate dose levels which produce improved responses in patients while simultaneously minimizing the adverse side effects a patient may experience. After taking into account a patient's age, weight, and other factors specific to the patient, the physician will prescribe an initial dose which may be increased or decreased as needed, depending on how the patient responds. This titration continues until a favorable balance between the desired response and undesirable side effects is achieved.
The difficulty arrives in attempting to translate this approach to determining dosages in the case where multiple drugs and/or other treatment modalities are being prescribed in the treatment of a single disease, or where the consideration of multiple endpoints is needed in the case where a single treatment is prescribed. There is currently no systematic or efficient method for determining dosages in multi-drug regimens. The physician generally either chooses to address the problem empirically, or will employ an ad-hoc approach, varying the levels of one drug while keeping the doses of all the other drugs in the combination fixed. Unfortunately, this approach does not account for potential interactions among the drugs, which may be crucial when searching for the most desirable therapy.
Not only is combination dosing difficult for practicing physicians in the day-to-day care of their patients, but it also presents a problem in both clinical trials research and drug evaluation research. For example, in the evaluation of a novel two-drug combination, which is composed of a new therapy plus the standard therapy, a typical approach which may be used is to randomize half of the subjects to the standard drug group and the other half to the two-drug combination. There are several problems with this approach. The first problem is that if no difference in response is found between the groups, this does not necessarily mean that the new combination is ineffective. The lack of effect may lie in the dose chosen for use in the study. Secondly, this approach does not provide any information regarding the location of more effective doses if the combination is not found to differ from the standard. On the other hand, if the new combination is found to be more effective, approximately half the subjects enrolled in the study, those randomized to the standard treatment, have not benefitted from the trial. Finally, even with early stopping rules, the time a patient spends on the inferior treatment can have lasting detrimental effects. These problems can lead to difficulties with patient recruitment and adherence to the study protocol.
Outside of the clinical trials arena, a common approach which has been used to evaluate combination therapies is the use of response surface methodology (RSM). With this approach, an experiment is carried out using a grid of fixed dose combinations. The fixed combinations are administered to subjects, often using a factorial design, and the response is observed over the range of dose combinations. The resulting response surface can then be used to identify areas of improved response. While this is a somewhat effective approach, it is limited in its application for several reasons. Firstly, this approach requires the use of predetermined, fixed combinations, none of which may actually correspond to the best treatment. Also, the ideal treatment may lie entirely outside of the range of doses used in the study. Furthermore, these studies quickly become expensive due to the numerous dose combinations required. Finally, RSM requires the pre-specification of the dose-response relationship, which is usually unknown. This requires an additional assumption that the dose-response relationship is well approximated by the equation specified.
It would be highly desirable to have available a systematic and efficient, yet practical and flexible, method for titrating in individual patients treatment regimens comprised of multiple modalities, and for evaluating the efficacy of such multi-modality therapies.